tbuckley/cabot-search huggingface dataset:
Abstract 10769: Circulating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension
Authors: Shengyuan Luo, Aditya Surapaneni, Casey Rebholz, Lawrence J Appel, Josef Coresh, Morgan Grams
Journal: Circulation (2022)

Introduction: Branched-chain amino acids (BCAAs), i.e., leucine, isoleucine, and valine, are involved in glucose regulation, immunity, and cell signaling. Higher circulating BCAAs were associated with incident cardiovascular disease (CVD) in the general population which may be mediated by insulin resistance. BCAA’s role in CVD in the absence of diabetes is unclear. Hypothesis: BCAAs are associated with cardiovascular outcomes in non-diabetic chronic kidney disease (CKD), a highly prevalent condition that substantially alters circulating metabolites and elevates CVD risk. Methods: In the African American Study of Kidney Disease and Hypertension (AASK), we conducted serum metabolomic profiling and assessed associations between BCAAs and risks for incident CVD (hospitalization for nonfatal myocardial infarction, cardiac revascularization, heart failure, stroke, or cardiovascular death), cardiovascular death, and all-cause mortality using multivariable Cox regression. Results: In 962 participants (mean age 56 years, 39% women, mean glomerular filtration rate [GFR] 48 ml/min/1.73m 2 , mean fasting blood glucose 94 mg/dl, mean low density lipoprotein cholesterol [LDLc] 137 mg/dl), BCAAs were minimally correlated with GFR, proteinuria, C-reactive protein, LDLc, or blood glucose. During follow-up (median 7.4 years), there were 192 CVD events (myocardial infarction or revascularization, n=57; stroke, n=74; heart failure, n=74) and 220 deaths of which 54 were cardiovascular deaths. Adjusted for covariates, no association was found between BCAAs and incident CVD, but higher BCAAs were associated with lower cardiovascular death (per doubling BCAA, HR=0.52, 95%CI 0.31-0.87; p=0.013 for isoleucine; HR=0.30, 95%CI 0.13-0.68, p=0.004 for leucine, HR=0.39, 95%CI 0.16-0.94, p=0.04 for valine). Associations were unchanged accounting for all-cause death as competing risk using Fine-Gray modeling. Leucine and isoleucine were associated with lower all-cause mortality (HR=0.57, 95%CI 0.36-0.96, p=0.035 for leucine; HR=0.70, 95%CI 0.49-1.00, p=0.049 for isoleucine). Conclusions: In African Americans with non-diabetic CKD, higher circulating BCAAs were associated with lower cardiovascular death, lower mortality, but not incident CVD.
Abstract 10583: A Critical Contribution of Cardiac Myofibroblasts in Rv Failure and the Role of Ucp2 Snps in the Predisposition to Rv Decompensation in Pulmonary Arterial Hypertension
Authors: Yongneng Zhang, Maria A Lorenzana Carrillo, Mahsa Mohseni, Saymon Tejay, Yongsheng Liu, Alois S Haromy, Gopinath Sutendra, Evangelos D Michelakis
Journal: Circulation (2022)

Introduction: The compensatory stage in right ventricle hypertrophy (RVH) in pulmonary arterial hypertension (PAH) is much shorter than in left ventricle hypertrophy (LVH) in systemic hypertension. Between 2 patients with the same degree of PAH one may have a much shorter compensated RVH (cRVH) stage than the other. The cardiac myofibroblasts (CMF) may contribute to these differences. Their ability to contract (stiffening), produce collagen and promote inflammation contributes to heart failure. Decreased mitochondrial calcium (mCa++) promotes CMF differentiation (from cardiac fibroblasts). Methylation of the mCa++ Uptake 1 (MICU1) and lack of UCP2 (uncoupling protein 2, a component of the mCa++ uniporter complex) activate CMF in the LV. Hypothesis: RV CMF are major contributors to RV failure in PAH, and loss of CMF-UCP2 promotes myofibroblast activation and RV decompensation. Methods: In a rat PAH model (Monocrotaline-PAH), we measured the RV pressure from isolated perfused hearts and sarcomere shortening from isolated RV cardiomyocytes. In a cohort (n=25) of patients with pulmonary hypertension that had been treated with the same protocol for years and controlled for age/sex/duration of disease, the correlation between UCP2 loss-of-function SNPs and RV function was measured. Results: In isolated hearts, RV pressure is lower in decompensated RVH (dRVH) compared to normal RV, but in vitro there is no difference in cardiomyocyte sarcomere shortening between the two groups, pointing to potential detrimental role of RV CMF rather than contractile failure of RV cardiomyocytes. dRVH has much more CMF compared to normal RV. CMF from dRVH have increased MICU1 methylation and decreased UCP2 levels compared to normal RV fibroblasts. PAH patients with homozygotes for UCP2 SNPs have worse RV function compared to heterozygote or wild-type, despite similar PA pressures. Conclusions: Our preliminary work suggests that RV CMF rather than RV cardiomyocytes may drive RV decompensation independent of RV afterload in PAH patients and this may be predicted by UCP2 SNPs that are relatively frequent in the population and have been shown to be associated with PAH outcomes (10-year survival, time to transplantation).
Abstract 10935: Long-Term Maturity and Extensibility of an <i>In S</i> <i>itu</i> Regenerated Aortic Wall Induced by a Novel Synthetic Hybrid Knit
Authors: Shintaro Nemoto, Hayato Konishi, Tatsuya Suzuki, Akiyo Suzuki, Takahiro Katsumata, Ayuko Yamaguchi, Kiyoe Hibino, Takeshi Sakaue
Journal: Circulation (2022)

Introduction: A novel synthetic hybrid warp-knit with non-biodegradable (polyethylene terephthalate: PET) and biodegradable (poly-L-lactic acid: PLLA) yarns coated with crosslinked gelatin (OFT) has been used to induce in situ canine aortic wall regeneration. A recent pivotal clinical trial in Japan revealed the effectiveness and safety of this approach in pediatric cardiac surgery. Hypothesis: The regenerated aortic wall will show long-term extensibility with tissue maturation as the biodegradable yarns dissolve. Methods: An oval-shaped defect created in the canine descending aorta was filled with a patch using OFT or a currently used material (ePTFE or bovine pericardium). At 2 to 4 years after implantation, the patch-implanted aorta was explanted for histological examination and stretch-testing. Results: OFT induced a well-matured aortic wall characterized by a layered endothelium and an intima of aligned collagen fibers and smooth muscle. Bridging tissues containing capillaries developed across the remaining non-absorbable yarns. Material degradation indicated by calcium deposition was not apparent in the OFT-regenerated wall, but was clear in walls generated by currently used materials, in which only avascular collagen layers developed. The OFT-regenerated wall maintained physiological strength and was extensible by 80 to 200% of the starting width. Conclusions: The aortic wall regenerated over the OFT patch continued to mature without material degradation in the long term and showed favorable extensibility that could not be achieved with currently used materials. These long-term findings provide strong support for the suitability of use of OFT as a surgical material in pediatric cardiac surgery.
Abstract 10470: Projected Lifetime Benefits of Alirocumab in Patients After Acute Coronary Syndrome
Authors: Andrzej Budaj, Yedid Elbez, Gregory G Schwartz, Deepak L Bhatt, Vera A Bittner, Terrance Sing Jin Chua, Rafael Diaz, Shaun G Goodman, Robert A Harrington, J Wouter Jukema, Sasko Kedev, Alexander Laucevicius, JOAO MORAIS, Jan MURIN, Alexander Parkhomenko, Robert Pordy, Michel Scemama, Michael Szarek, Harvey D White, Philippe G Steg
Journal: Circulation (2022)

Introduction: In the ODYSSEY OUTCOMES trial, alirocumab improved cardiovascular outcomes and reduced death after acute coronary syndrome (ACS). Median follow-up was 2.8 yrs (range 2-5). The effects of alirocumab on long-term survival are unknown. Objective: To calculate projected life span and potential survival gains with alirocumab vs placebo after ACS using validated nonparametric age-based methods. Methods: In ODYSSEY OUTCOMES (NCT01663402), 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite high-intensity or maximum-tolerated statin therapy were randomized to alirocumab or placebo. All-cause death was a secondary trial outcome. Age-based estimates of projected survival and event-free (all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke) survival were calculated. In each treatment arm at every year of age, lifespan was estimated from area under the survival curve, to a maximum of 85 yrs. Differences in areas under the survival curves provide an estimate of the benefit of alirocumab on survival. Results: Mean (SD) baseline age was 58.5 (9.3) yrs. Mean survival benefits with alirocumab vs placebo ranged from 0.03 to 1.62 yrs, decreasing with age and becoming neutral at age 80-85 yrs. For example, at age 40, estimated survival was another 37.5 yrs with alirocumab and 35.9 yrs with placebo (difference 1.62 yrs [95% CI, 0.30-2.94]; P =0.016). At age 60, it was 20.5 vs 19.6 yrs (difference 0.88 [95% CI, 0.16-1.61]; P =0.017); at age 75 it was 8.8 vs 8.3 (difference 0.57 [0.09-1.05]; P =0.019); and at age 80, it was 4.5 vs 4.5 years (difference 0.03 [-0.28 to 0.35]; P =0.83). Mean event-free survival benefit similarly ranged from 1.85 to 0.0 yrs. Conclusions: Modeling suggests that long-term treatment with alirocumab may result in a meaningful increase in survival among patients less than 80 yrs of age. This analysis may facilitate shared decision-making with patients. Funding: Sanofi, Regeneron Pharmaceuticals
Abstract 10296: Relation of Lipoprotein(a) to Progression of Coronary Artery Calcium: Results From a Pooled Cohort of Mesa, Cardia, and Framingham Offspring Studies
Authors: Nathan D Wong, WENJUN FAN, Xingdi Hu, Christie M Ballantyne, Ron C Hoogeveen, Michael Y Tsai, Auris Browne, Matthew Budoff
Journal: Circulation (2022)

Background: Lipoprotein(a) [Lp(a)] levels and coronary artery calcium (CAC) are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. Progression of CAC is also associated with greater ASCVD risk. Less well-established is the relation of Lp(a) with progression of atherosclerosis as assessed by progression of CAC. Methods: We included a pooled cohort of 9454 persons without ASCVD at baseline (mean age 55.6 years, 53.5% female, and 31% black) and with multiple measures of CAC (up to 4 over a mean of 7.3 + 3.3 years from baseline CAC measures) from the Multiethnic Study of Atherosclerosis, Coronary Artery Risk Development in Young Adults, and Framingham Offspring Studies. Lp(a) was assessed continuously and by category (&lt;15 mg/dL [reference], 15-29 mg/dL, 30-49 mg/dL, 50-69 mg/dL, 70-89 mg/dL, and &gt; 90 mg/dL) in relation to progression of CAC (annualized change in Agatston score) incorporating multiple CAC measures utilizing mixed model regression with time (in years), adjusted for age, sex, race, baseline CAC, and other covariates. Subgroup analyses were done separately in those with baseline CAC. Results: A 50 mg/dL increment of Lp(a) was associated with an adjusted annualized change in CAC score of 3.97 units. Compared to those with Lp(a) levels of &lt;15 mg/dL, those with levels of 50-69 mg/dL, 70-89 mg/dL, and &gt; 90 mg/dL had a statistically significant annualized progression of CAC that was 3.09, 8.70, and 9.46 units greater in adjusted analyses. Progression was greater in those with baseline CAC&gt;0 (Table). Conclusions: Higher levels of Lp(a) are associated with greater progression of atherosclerosis as measured by CAC scores.
Abstract 10946: Myocardial Inflammatory Activity and Oxidative Stress Immunosuppressive Therapy Are Associated With Prognosis in Patients With Cardiac Sarcoidosis
Authors: Yusuke Nakashima, Shigeki Kobayashi, Maho Ishikawa, Ishiguchi Hironori, Masakazu Fukuda, Takeshi Suetomi, Yousuke Miyazaki, Tatsuhiro Fujiura, Hitoshi Uchinoumi, Mamoru Mochizuki, Takayuki Okamura, Masafumi Yano
Journal: Circulation (2022)

Background: P atients with cardiac sarcoidosis (CS) have been shown to be at an increased risk of major adverse cardiovascular events (MACE). Enhancement in myocardial inflammatory activity and oxidative stress is a crucial cause of MACE. Immunosuppressive therapy is recommended for the treatment of active CS. After immunosuppressive therapy, however, there is no predictable markers for prognosis. We hypothesized that the inflammation and oxidative stress in heart were associated with MACE. Aim: We identified prognostic markers for MACE in patients with CS after steroid therapy. Methods: This prospective cohort study enrolled 103 consecutive patients with CS diagnosed according to the Japanese guideline; Of 103 CS patients, 39 patients underwent 18F-FDG PET/CT 6 months after steroid therapy, and levels of urinary 8-hydroxy-2′-deoxyguanosine (U-8-OHdG) as a marker of oxidative DNA damage, other biomarkers, indices of cardiac function, and renal function were measured. Then they were followed up for a median of 42 months. The primary endpoint was a composite of the first sustained ventricular tachycardia (sVT) /sudden cardiac death (SCD), hospitalization for heart failure, and worsening CS with increased accumulation of FDG in heart and exacerbation of clinical manifestation. Results: During the follow-up period, 7 of 30 patients showed sVT/SCD (N= 9), hospitalization (N= 2) and worsening CS (N= 4). A Cox proportional-hazard model showed that U-8-OHdG concentration and SUV max value of FDG-PET were independent predictors of MACE. ROC analysis showed that the cut-off values of U-8-OHdG and SUV max for predicting the MACE were 14.2 ng/mg·Cr and 4.6 respectively. Patients with a U-8-OHdG ≥ 14.2 ng/mg·Cr or SUV max ≥4.6 had a significantly higher MACE risk (Figure A and B). Conclusions: U-8-OHdG and SUV max after steroid therapy were powerful predictors of MACE in CS, suggesting that CS patients with high U-8OHdG and/or high SUV max might be resistant to steroid therapy.
Abstract 10413: Obesity Modifies Clinical Outcomes of RV Dysfunction
Authors: Janet Ma, Emily Zern, Dongyu Wang, Paula Rambarat, Eugene Pomerantsev, Michael Picard, Jennifer E Ho
Journal: Circulation (2022)

Introduction: Right ventricular (RV) dysfunction is associated with increased mortality across a spectrum of cardiovascular diseases. Whether this association is modified by obesity is unclear. We examined the association of obesity with hemodynamic indices of RV function, and subsequent outcomes. Hypothesis: We hypothesized that obesity is associated with RV dysfunction, and that obesity modifies the association of RV dysfunction with adverse clinical outcomes. Methods: We examined patients undergoing right heart catheterization between 2005-2016 in a hospital-based cohort. Linear regression was used to examine the association of obesity with hemodynamic indices of RV dysfunction [pulmonary artery pulsatility index (PAPi), right atrial pressure: pulmonary capillary wedge pressure ratio (RAP:PCWP), RV stroke work index (RVSWI)]. Cox models examined the association with clinical outcomes. Results: We studied 8285 patients (mean age 63 years, 40% women). Higher BMI was associated with worse indices of RV dysfunction, including lower PAPi (β -0.26, SE 0.01, p &lt;0.001) and higher RA:PCWP ratio (β 0.25, SE 0.01, p-value &lt;0.001) but not RVSWI (p&gt;0.05). Over 7.3 years of follow-up, we observed 3006 mortality and 2004 heart failure (HF) hospitalization events. RV dysfunction was associated with greater risk of mortality (PAPi: HR 1.11 per 1-SD increase, 95% CI 1.04-1.18; RA:PCWP ratio: HR 0.84, 95% CI 0.79-0.90), with similar associations with risk of HF hospitalization. Furthermore, BMI modified the effect of RV dysfunction on outcomes (P-interaction &lt;=0.005 for both), and the effect of RV dysfunction was more pronounced at higher BMI. Conclusions: Patients with obesity had worse indices of RV function, including lower PAPi and higher RAP:PCWP ratio. While RV dysfunction was associated with worse clinical outcomes, this association was especially pronounced among individuals with higher BMI.
Abstract 10196: Reducing Symptom Burden Using Ubiquinol And/Or D-Ribose in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Janet D Pierce, Qiuhua Shen, Diane Mahoney, Francisco Diaz, Carol E Smith, Faith Rahman, Kathryn Krueger, Lauren Clark, John B HIEBERT
Journal: Circulation (2022)

Introduction: Mitochondrial dysfunction has been implicated in the development of HFpEF, particularly a decrease in the production of adenosine triphosphate (ATP). Ubiquinol is produced in the mitochondria and is required for oxidative phosphorylation and D-ribose is an essential component of ATP. Thus, supplementing with ubiquinol and/or D-ribose could be useful to improve mitochondrial biomechanics and patient symptoms. Hypothesis: To determine if ubiquinol and/or D-ribose would reduce the symptoms and improve cardiac performance in patients with HFpEF. Methods: This study was a randomized, double-blind, placebo-controlled trial of 216 patients with HFpEF. Four study groups received various supplements over 12 weeks: Group 1 - placebo capsules and placebo powder (placebo group); Group 2 - ubiquinol (600 mg/day) and placebo D-ribose; Group 3 - placebo ubiquinol with D-ribose (15 g/day); Group 4 - ubiquinol (600 mg/day) and D-ribose (15 g/day). There were seven outcome measures for this study: Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS), level of vigor using a subscale from the Profile of Mood States (POMS), ejection fraction (EF), the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (eꞌ) (septal E/eꞌ ratio), B-type natriuretic peptides (BNP), lactate/ATP ratio, and the 6-minute walk test (6MWT). Results: Using ubiquinol and/or D-ribose significantly increased the KCCQ clinical summary score (17.30 to 25.82 points [compared to Group 1, p = 0.0001 (Group 2); p &lt; 0.0001 (Group 3); p=0.0116 (Group 4)], vigor score (7.65 to 8.15 points [all p &lt; 0.0001]), EF (7.08 to 8.03% [p = 0.0006; p &lt; 0.0001; p = 0.0002]), and decreased BNP (-72.02 to -47.51 pg/mL [p = 0.0002; p = 0.0024; p = 0.0415]) and lactate/ATP ratio (-4.32x10 -4 to -3.35x10 -4 mmol/L/RLU) [p &lt; 0.0001; p &lt; 0.0001; p = 0.0006]). We found no significant improvement in septal E/e’ or 6MWT. Conclusions: The use of ubiquinol and/or D-ribose significantly decreased the patients’ symptoms of HFpEF and improved EF. This suggests that the ubiquinol and/or D-ribose increased mitochondrial function by increasing cellular ATP &amp; may help reduce symptom burden and improve cardiac function. NIH: 1R01AG054486-01A1, NCT03133793, IND: 134633
Abstract 10401: Development and Pilot Implementation of Two Targeted Approaches to Ambulatory Clinical Decision Support for Cardiologists to Optimize Medical Therapy for Heart Failure
Authors: Amrita Mukhopadhyay, Harmony Reynolds, Yuhe Xia, Lawrence M Phillips, Rod Aminian, Ruth-Ann Diah, Arielle Nagler, Adam Szerencsy, Archana Saxena, Leora Horwitz, Stuart D Katz, Saul Blecker
Journal: Circulation (2022)

Introduction: Shortfalls in prescribing of proven therapies for patients with heart failure and reduced ejection fraction (HFrEF), particularly for mineralocorticoid receptor antagonists (MRA), account for several thousand preventable deaths per year nationwide. Electronic clinical decision support (CDS) is a potential low-cost and scalable solution to improve prescribing, but optimal timing and format of CDS tools are unknown. Objective: We developed two CDS interventions to inform cardiologists of gaps in MRA therapy for patients with HFrEF and without contraindication to MRA therapy: 1) a best practice alert (BPA) that notifies cardiologists at the time of patient visit, and 2) an automated in-basket message that allows for review between visits. Methods: We designed CDS tools using an established CDS framework and findings from semi-structured interviews with cardiologists. We then pilot-tested both CDS tools at two cardiology practices for 12 weeks in a cross-over design, and further enhanced them based on additional semi-structured interviews. Results: Based on pilot testing (n=596 patients) and semi-structured interviews (n=11 cardiologists), in-basket messages were modified to reduce the number of patients listed, include future visits, and list date of next visit. The BPA was modified to improve noticeability, reduce extraneous information on guidelines, and include key information on contraindications. Final CDS interventions after incorporation of feedback are depicted in the Figure. Conclusions: Pilot testing and semi-structured interviews were instrumental in the development of CDS interventions and should be employed for other similar studies. We will compare the effectiveness of the BPA vs the in-basket message vs usual care on the primary outcome of MRA prescribing in The BETTER CARE-HF trial (Building Electronic Tools to Enhance and Reinforce CArdiovascular REcommendations for Heart Failure) (Clinicaltrials.gov NCT05275920)
Abstract 10370: Effects of Tirzepatide on 24-Hour Ambulatory Blood Pressure and Heart Rate in Adults With Obesity - Results From the SURMOUNT-1 Ambulatory Blood Pressure Monitoring Sub-Study
Authors: James A De Lemos, Carel W le Roux, Huzhang Mao, Nadia N Ahmad, shuyu zhang, Mathijs Bunck, Adam Stefanski
Journal: Circulation (2022)

Background: Tirzepatide has demonstrated substantial reductions in body weight and in-office blood pressure (BP) in people with obesity with and without type 2 diabetes (T2D). The effects of tirzepatide on ambulatory BP and heart rate (HR) have not been evaluated. We sought to assess the effect of tirzepatide on 24-hour (24h) mean systolic BP (SBP), diastolic BP (DBP) and HR, as measured during 24h ambulatory BP monitoring (ABPM) in people living with obesity without T2D. Methods: In the SURMOUNT-1 ABPM sub-study, participants with a body mass index ≥30, or ≥27 kg/m 2 and at least one weight-related complication (excluding diabetes), with SBP/DBP &lt;140/90 mmHg (and stable antihypertensive therapy if used), were randomly assigned 1:1:1:1 to once-weekly subcutaneous tirzepatide 5, 10, or 15 mg or placebo. The randomization was stratified by pre-diabetes status, country, sex, and use of heart rate controlling medicines at baseline. Participants underwent 24h ABPM at baseline and after 36 weeks of treatment. Results: Among participants randomized in the SURMOUNT-1 trial, 600 were enrolled in the ABPM substudy (69% female; mean age 46 y, BMI 37 kg/m 2 ). No clinically significant between-treatment differences were observed in baseline characteristics. Overall, 494 participants had evaluable ABPM data at baseline and post-baseline. Treatment with all tirzepatide doses was associated with significant reductions in 24h SBP at 36 weeks compared with placebo. Participants who received tirzepatide 5 and 10 mg, but not 15 mg, had significantly reduced 24h DBP at 36 weeks versus placebo. An increase in 24h HR was observed with each tirzepatide dose relative to placebo. Conclusion: After 36 weeks of treatment, tirzepatide was associated with statistically significant and clinically meaningful reductions in mean 24h SBP at all doses and of DBP at the two lower doses. Tirzepatide treatment was associated with a dose-dependent increase in the mean 24h HR.